The enzyme angiotensin converting enzyme (ACE) catalyses the hydrolysis of the deca-peptide Angiotensin I to the octapeptide Angiotensin II. The latter contributes to a number of physiological mechanisms that lead to the elevation of blood pressure. Many of these mechanisms are initialized by the binding of Angiotensin II to the Angiotensin receptor AT1.
A number of inhibitors of the binding of Angiotensin II to this receptor are known—for example valsartan, losartan, irbestan, candesartan cilexetil, tasosartan, telmisartan, eprosartan, zolasartan and saprisartan. By blocking of the binding and thus the activation of the AT1 receptor, these active compounds are able to lower blood pressure. These and other comparable compounds are therefore commonly referred to as angiotensin II receptor antagonists or more recently as angiotensin receptor blockers (ARBs).
Except for telmisartan, eprosartan and saprisartan, the mentioned compounds share a common structural feature in the form of a pharmacophore of the following partial formula A,
where the waved line indicates the place of binding to the rest of the molecule (which may also be present in tautomeric form, either in equilibrium or totally, with the hydrogen at the tetrazolyl ring at the 1-instead of the 2-position of that ring; the same also is true for any compound mentioned below where such tautomerism is possible and will therefore not be mentioned specifically in any case).
PCT application WO 05/014602 A1 describes a process for the manufacture of intermediates useful in the synthesis of this common moiety and the final pharmaceutically active compounds, such as the ARBs mentioned above, e.g. valsartan. There, the synthesis of an aldehyde of the formula I,
is described which is further reacted to various pharmaceutically active substances such as the ARBs, e.g. valsartan, directly or via one or more further reaction steps and intermediates.
In a reaction described in WO 2005/014602, the crude product of the formula I obtainable after oxidation of the hydroxymethyl precursor to the aldehyde of the formula I is used in a subsequent reductive amination, for example, with L-valine.
When the aldehyde of the formula I is produced and used in the subsequent reaction step, this, in the case of production in industrial scale, comprises a significant amount of water, that is, up to now it has been regarded as convenient to use said aldehyde in “wet” form.
A problem to be solved by the present invention is to find a yet improved process and/or intermediates that allow for an improved process of manufacture of ARBs, especially valsartan, that is especially useful for manufacturing processes in an industrial scale.